Calcium- a;nd phospholipid-dependent protein kinase (PK-C) activity was determined in association with the differentiation response of HL-60 leukemia cells to DMSO, retinoic acid, 1,25-dihydroxyvitamin D3, phorbol ester (TPA) and interferon-Gamma. PK-C activity rose in proportion to the appearance of the mature granulocytic or monocytic phenotype. Conditions under which TPA produced the macrophage phenotype resulted in disappearance of PK-C, but duplication of this phenotypic response with one hour priming doses of TPA and post treatment with retinoic acid showed conclusively that down regulation of PK-C is not a necessary consequence of the macrophage phenotype. A new investigation has been initiated to study the regulation of plasma membrane-associated tyrosine kinase in HL-60 leukemia cells undergoing differentiation and in cells resistant to differentiating agents. In addition, the relationship between membrane tyrosine kinase and pleiotropic drug resistance in human breast carcinoma cell line MCF-7 is being investigated to assess the association between the p170 glycoprotein induced in multidrug resistant cells, calcium channels and tyrosine kinase. To investigate these problems, a new nondenaturing gel electrophoretic assay for multiple tyrosine kinase activities in cell extracts has been developed.